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J. Biol. Chem., Vol. 279, Issue 14, 13289-13292, April 2, 2004

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ACCELERATED PUBLICATIONS

Impairment of HERG K⁺ Channel Function by Tumor Necrosis Factor-

ROLE OF REACTIVE OXYGEN SPECIES AS A MEDIATOR^*

Jingxiong Wang¶||, Huizhen Wang¶, Yiqiang Zhang**, Huanhuan Gao, Stanley Nattel, and Zhiguo Wang¶¶

From the Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, the Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, and the Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3A 2T5, Canada

Congestive heart failure (CHF) is associated with susceptibility to lethal arrhythmias and typically increases levels of tumor necrosis factor- (TNF-) and its receptor, TNFR1. CHF down-regulates rapid delayed-rectifier K⁺ current (I_Kr) and delays cardiac repolarization. We studied the effects of TNF- on cloned HERG K⁺ channel (human ether-a-go-go-related gene) in HEK293 cells and native I_Kr in canine cardiomyocytes with whole-cell patch clamp techniques. TNF- consistently and reversibly decreased HERG current (I_HERG). Effects of TNF- were concentration-dependent, increased with longer incubation period, and occurred at clinically relevant concentrations. TNF- had similar inhibitory effects on I_Kr and markedly prolonged action potential duration (APD) in canine cardiomyocytes. Immunoblotting analysis demonstrated that HERG protein level was slightly higher in canine hearts with tachypacing-induced CHF than in healthy hearts, and TNF- slightly increased HERG protein level in CHF but not in healthy hearts. In cells pretreated with the inhibitory anti-TNFR1 antibody, TNF- lost its ability to suppress I_HERG, indicating a requirement of TNFR1 activation for HERG suppression. Vitamin E or MnTBAP (Mn(III) tetrakis(4-benzoic acid) porphyrin chloride), a superoxide dismutase mimic) prevented, whereas the superoxide anion generating system xanthine/xanthine oxidase mimicked, TNF--induced I_HERG depression. TNF- caused robust increases in intracellular reactive oxygen species, and vitamin E and MnTBAP abolished the increases, in both HEK293 cells and canine ventricular myocytes. We conclude that the TNF-/TNFR1 system impairs HERG/I_Kr function mainly by stimulating reactive oxygen species, particularly superoxide anion, but not by altering HERG expression; the effect may contribute to APD prolongation by TNF- and may be a novel mechanism for electrophysiological abnormalities and sudden death in CHF.

Received for publication, January 16, 2004 , and in revised form, February 6, 2004.

^* This work was supported in part by the Heart and Stroke Foundation of Canada and Fonds de la Recherche de l'Institut de Cardiologie de Montreal (awarded to Z. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this study.

^|| A recipient of Doctoral-Studentship of the Fonds de Recherche en Sante de Quebec.

^** A recipient of Doctoral-Studentship of the Heart and Stroke Foundation of Canada.

Current Address: Dept. of Physiology, McGill University, Montreal, Quebec H3A 2T5, Canada.

^¶¶ A research scholar of the Fonds de Recherche en Sante de Quebec. To whom correspondence should be addressed: Research Center, Montreal Heart Inst., 5000 Belanger East, Montreal, Quebec H1T 1C8, Canada. Tel.: 514-376-3330; Fax: 514-376-4452; E-mail: wangz{at}icm.umontreal.ca.

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